Congenital Anomaly and Perinatal Outcome Following Blastocyst- Vs Cleavage-stage Embryo Transfer: Systematic Review and Network Meta-analysis

Objectives: To compare the reported rate of any congenital anomaly and perinatal outcome of pregnancy following blastocyst- vs cleavage-stage embryo transfer using a pairwise meta-analysis and to evaluate the same outcomes following fresh-blastocyst, frozen-blastocyst, fresh-cleavage or frozen-cleavage embryo transfer using a network meta-analysis.

Methods: A literature search was performed in PubMed, Scopus and CENTRAL and registers for ongoing studies, from inception to February 2022, for randomized controlled trials (RCTs) with any sample size and observational studies including at least 100 live births per group, comparing the rates of any congenital anomaly and perinatal outcome of pregnancy following fresh/frozen embryo transfer at cleavage (day 2-3) vs blastocyst (day 5-7) stage. Risk ratios (RRs) along with their 95% CIs were pooled via a random-effects model meta-analysis. Within a frequentist network meta-analysis framework, outcomes of all four treatment modalities (i.e. fresh-blastocyst, fresh-cleavage, frozen-blastocyst, frozen-cleavage) were compared further. Any congenital anomaly constituted the primary outcome, whereas preterm delivery (delivery < 37 weeks), low birth weight (LBW; < 2500 g), gender of the neonate (male), perinatal death and healthy neonate (defined as liveborn neonate, delivered at term, weighing ≥ 2500 g, surviving for at least 28 days postbirth and without any congenital anomaly) were considered as secondary outcomes. Subgroup analyses by plurality (liveborn singleton vs multiple pregnancy) were conducted in the pairwise and network meta-analyses. The risk of bias was assessed using the RoB2 tool for RCTs and the ROBINS-I tool for non-randomized studies. Certainty of evidence was assessed using GRADE.

Results: Through the literature search, 550 studies were retrieved and 33 were included in the systematic review. We found no significant difference in the risk for any congenital anomaly between blastocyst- and cleavage-stage transfer (RR, 0.80 (95% CI, 0.63-1.03); 10 studies; n = 192 442; I  = 85.5%). An increased probability of a male neonate was observed following blastocyst- vs cleavage-stage transfer (RR, 1.07 (95% CI, 1.06-1.09); 18 studies; n = 227 530; I  = 32.7%). No significant differences in other secondary outcomes or significant subgroup differences between liveborn singletons and multiple pregnancies were observed. The network meta-analysis showed a significantly lower risk for LBW following frozen-blastocyst vs fresh-blastocyst (RR, 0.76 (95% CI, 0.60-0.95)) or fresh-cleavage (RR, 0.74 (95% CI, 0.59-0.93)) transfer. Frozen-blastocyst transfer was associated with an increased risk for perinatal death compared with the fresh-cleavage method (RR, 2.06 (95% CI, 1.10-3.88)). The higher probability of a male neonate following blastocyst transfer remained evident in the network comparisons. All outcomes were assessed to be of very-low certainty of evidence.

Conclusions: Current very-low certainty of evidence shows that there may be little-to-no difference in the risk for congenital anomaly or adverse perinatal outcome of pregnancy following blastocyst- vs cleavage-stage embryo transfer, although there was a slightly increased probability of a male neonate following blastocyst transfer. When considering cryopreservation, frozen-blastocyst transfer was associated with a reduction in the risk for LBW compared with both fresh-transfer modalities, and fresh-cleavage transfer may be associated with a reduction in the risk for perinatal death compared with frozen-blastocyst transfer. High-quality RCTs with separate data on fresh and frozen cycles and consistent reporting of culture conditions and freezing methods are mandatory. Individual participant data meta-analyses are required to address the substantial inconsistency resulting from current aggregate data approaches. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.